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Streamlining the Pipeline

Big pharma is worried. Despite throwing more money than ever at research and development (R&D)--global R&D spending increased by 75% in the 10 years prior to 2001 *--companies are finding that those blockbuster drugs that provide return on the investment seem to be harder and harder to come by. Just 31 new molecular entities were launched in 2001, compared with 52 in 1991. * That's partly because legislative hurdles are making it harder to bring new drugs to market, but finding them in the first place is getting tougher, too. The drug-discovery pipeline's output has slowed to a trickle.

But in one of the shiny glass and chrome buildings of the University of Helsinki's new Viikki campus, there's a group of scientists who are hoping to find ways of getting promising drug candidates into the clinic more swiftly--and more cheaply. Their in vitro experiment--which they call the Drug Discovery Technology Center (DDTC)--involves mixing researchers from backgrounds as varied as chemistry, molecular biology, engineering, and technology and then watching the reaction.

Back in 1998, this center was just the spark of an idea. The draft of the human genome sequence was nearing completion, propelling a huge gearing up in the field of proteomics, but all this "is nothing without drugs," says Risto Kostiainen, head of DDTC. Meanwhile, he adds, "we had here in the Department of Pharmacy a lot of different technologies and skills," but they were all very isolated, which made no sense, considering Kostiainen's description of drug discovery: "the original multidisciplinary area."

Reorganising at the start of 2000 into a seven-programme project (see DDTC's Research Programmes, below) that brings each stage of the drug-discovery process--from molecular modelling to formulation and drug delivery--under one roof within the Department of Pharmacy has given research there a huge boost, says Raimo Tuominen, who leads the Biological Evaluation Programme. "We're now in a different world than we were in 4, or even 3, years ago," he claims. That's not surprising, according to organic chemist and junior group leader Jari Yli-Kauhaluoma, who points out that "the most fruitful results will emerge when people [from different backgrounds] talk and interact."

DDTC's Research Programmes

Design and Synthesis

High-Throughput Screening

Early ADME (absorption, distribution, metabolism, elimination)

Drug-Delivery Systems and Formulation

Biological Evaluation

Analytical Laboratory

Molecular Biology Laboratory

That interaction is extremely appealing to Ingo Bichlmaier, who is doing his Ph.D. research in Yli-Kauhaluoma's design and synthesis group. "It's something I never saw or experienced" in his native Germany, he notes. "There, departments are very separated," and people from different groups don't know one another, whereas by contrast, "it's easy here to ask" for advice or to use facilities in other labs. He really enjoys the opportunities for "looking over the borders of your own subject."

Training young researchers like Bichlmaier was another motivation for setting up DDTC. "There is continuously a shortage of high-level researchers in this area," says Kostiainen, and several people from the center have already been snapped up by industry. The first Ph.D. students to have carried out their research entirely under the DDTC umbrella will graduate later this year, but several master's theses have already been completed. In addition, DDTC organises a number of short courses each year in cooperation with Finland's Graduate School in Pharmaceutical Research, and it plans to hold more in collaboration with other graduate schools, says Pia Vuorela, who heads DDTC's bioactivity screening group. A recent "Introduction to High-Throughput Screening Technology" attracted not just 30 Ph.D. students but also an additional 20 attendees from industry.

What industry needs, and what DDTC aims to deliver, is researchers who, while being specialists in one area, "understand the whole system," says Kostiainen. A training in drug-discovery technology is "training for anything," he suggests, because it gives one the opportunity to "utilise one's knowledge in very different fields," from synthesis to analysis. Even the "regulatory agencies are interested" in people with such a background, says Vuorela.

Kostiainen's experience is that this is a field with considerable appeal for young scientists, and not just because of the employment opportunities. For the entrepreneurially minded, drug-discovery technology is a "good platform for innovations" and an area that can produce patents (see Drug Discovery Entrepreneurs, below). Yli-Kauhaluoma suggests that this is partly because it's an area with "lots of space to work ... room to make your mark." Developing a new technique can have a huge impact on science, confirms Vuorela, citing the development of electrospray mass spectrometry in the late 1980s, without which "the whole of biotechnology wouldn't be at the stage it is today."

Drug-Discovery Entrepreneurs

DDTC has already produced its first start-up: Lead Pharmaceuticals. Founded by Jukka Takala and Antti Siiskonen, two postdocs from Jari Yli-Kauhaluoma's design and synthesis group, the company won the ?15,000 second prize in last year's national business plan competition, Venture Cup Finland. Carrying out drug discovery and development and lead identification and optimisation on behalf of larger companies, Lead Pharmaceuticals so far has just two employees--its founders!

DDTC is funded to the tune of approximately ?3.5 million annually, most of which comes from public sources: the University of Helsinki, Finland's National Technology Agency TEKES, the Academy of Finland, and the European Commission. But isn't this research that companies could and should be doing themselves? "Giant global companies can afford to do basic research," points out Tuominen, but "in Finland there are no such companies." Even so, DDTC has already transferred some of the technologies it has developed to small companies, says Kostiainen.

But there's a more fundamental reason why this kind of research is better suited to academia than to industry: "Their aim is drugs, our aim is technology," explains Kostiainen. That means that although companies "always have to validate" any changes to their methodology, which is a distraction from their primary goal, "we can change our methods" to find the optimum process, Kostiainen says.

Having an overview of the whole drug-discovery process should also give DDTC researchers an advantage when it comes to improving efficiency. One major problem is that "in vitro tests do not correlate very well with in vivo [ones]" says Kostiainen, and it's extremely expensive to bring a drug through to in vivo trials, only to discover deficiencies in its pharmacokinetic properties. Vuorela's group has taken up a project that aims to tackle this problem--developing whole cell-based assays. "You get much more information because [the drug is] already in a living environment," she explains. Can it, for example, actually reach its intracellular target? Is it cytotoxic? It is time-consuming to carry out such research. Moreover, because the assays involve "working with living material" and "cells are not identical," getting in vivo assays validated "is a big issue," Vuorela says.

Another problem, developing an automated assay environment that does not harm the cells, illustrates the benefit of the multidisciplinary approach--that's essentially an engineering issue, not a biological or chemical one. Nonetheless, Vuorela is convinced there is a future for her group's assay. "Industry is drawing back from high-throughput screening," says Vuorela, because it produces "too many errors."

But what does the future hold for DDTC? Cooperation with the Helsinki University of Technology, together with a number of other faculties, to launch a master's degree program in biotechnology this autumn will bring more engineers into the experimental mix. "To develop new technologies, you need the engineering sciences also," points out Vuorela, and the new master's program "will open totally new areas and possibilities." The University of Helsinki's continued support, meanwhile, depends upon a successful evaluation at the end of this year, although Kostiainen is confident that the success of DDTC's science will speak for itself. That will clear the way for the center to move into its own shiny new building, currently a bare patch of land across the street, in 2005. Although this will allow the center to "fill up several areas that we need," says Kostiainen, expansion plans are not huge, and the nucleus of researchers will remain at its current level of about 40. In a field where communication is so critical, small is beautiful, after all.